ABSTRACT Amyloid precursor-like protein 2 (APLP2) is a type I transmembrane protein that is highly conserved across mammalian species. Data from The Cancer Genome Atlas (NCI TCGA) shows that pancreatic adenocarcinoma patients whose tumors exhibit lower (compared to higher) levels of APLP2 have significantly better survival. By in vitro experiments and in vivo xenograft approaches, we found that APLP2 increases the growth, migration, and metastasis of pancreatic cancer cells. New RNA-Seq analysis also supports APLP2?s identity as a master regulator in the development of pancreatic adenocarcinoma. We showed that APLP2 is elevated in human and mouse pancreatic adenocarcinoma tissue samples, and that APLP2, as well as the fragments of APLP2 that are produced by the cleavage activity of the beta-secretase enzyme, are over expressed in pancreatic cancer cell lines. Chemical inhibitors of beta-secretase have been synthesized by multiple pharmaceutical companies because beta-secretase cleavage of a protein related to APLP2 (called amyloid precursor protein) is a step in the production of the beta-amyloid peptide implicated in Alzheimer?s disease progression. Several of these beta-secretase inhibitors are now in Phase III clinical trials for Alzheimer?s disease patients. These beta-secretase inhibitors also block APLP2 processing. We have found that treatment of pancreatic cancer cells with beta-secretase inhibitors results in APLP2 cleavage inhibition and decreased pancreatic cancer cell growth (without affecting growth of a non-transformed pancreatic cell line). In this project, we will test a beta-secretase inhibitor (in combination with standard pancreatic cancer chemotherapy) for therapeutic efficacy in orthotopic xenograft pancreatic cancer mouse models and in a genetically engineered mouse pancreatic cancer model, and we will investigate the mechanism underlying the efficacy of the therapeutic regimen. Our central hypothesis is that beta-secretase inhibitors (in combination with chemotherapy) will be effective against pancreatic cancer by influencing APLP2-linked pathways. Our Specific Aims are to: (1) evaluate in vivo the therapeutic effect of a beta-secretase inhibitor as a pancreatic cancer treatment in combination with chemotherapy, and (2) assess the role of an APLP2-linked signaling mechanism in beta-secretase inhibitor reduction of pancreatic cancer growth. We anticipate that the accomplishment of our Aims will contribute to the generation of novel treatments targeting APLP2 that will increase pancreatic cancer patient survival.